Synthesis and structure–affinity relationship of chlorinated pyrrolidinone-bearing benzenesulfonamides as human carbonic anhydrase inhibitors

• Published in: Bioorganic chemistry Vol. 97; p. 103658
• Main Authors: Balandis, Benas, Ivanauskaitė, Guostė, Smirnovienė, Joana, Kantminienė, Kristina, Matulis, Daumantas, Mickevičius, Vytautas, Zubrienė, Asta
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2020
• Subjects: 5-Oxopyrrolidine; Antigens, Neoplasm - metabolism; Benzenesulfonamide; Benzenesulfonamides; Carbonic anhydrase; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrase IX - antagonists & inhibitors; Carbonic Anhydrase IX - metabolism; Fluorescent thermal shift assay; Halogenation; Humans; Pyrrolidinones - chemistry; Pyrrolidinones - pharmacology; Structure-Activity Relationship; Structure-affinity relationship; Sulfonamides - chemistry; Sulfonamides - pharmacology; 5-Oxopyrrolidine; Structure-affinity relationship; Fluorescent thermal shift assay; Carbonic anhydrase; Benzenesulfonamide
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103658

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•Pyrrolidinone-bearing benzenesulfonamides with chlorine at position 3 were synthesized.•Compounds 12 and 15 exhibited low nanomolar dissociation constants for cancer-related isozyme CA IX.•Disulfonamide 3 was the most selective compound for CA II and exhibited 5 nM binding affinity.•Compounds 14 and 19 were the most potent binders of CA XIV (Kd = 3.3 nM).
A novel set of pyrrolidinone-based chlorinated benzenesulfonamide derivatives were synthesized and investigated for their binding affinity and selectivity against recombinant human carbonic anhydrases I–XIV using fluorescent thermal shift, p-nitrophenyl acetate hydrolysis and stopped-flow enzymatic inhibition assays. The hydrazones 10–22 prepared from 1-(2-chloro-4-sulfamoylphenyl)-5-oxopyrrolidine-3-carboxylic acid exhibited low nanomolar affinity against cancer-related CA IX (Kd in the range of 5.0–37 nM). Compounds with triazole or oxadiazole groups attached directly to pyrrolidinone moiety bound all CAs weaker than compounds with more flexible tail groups. Chloro group at the meta position of benzenesulfonamide derivatives increased affinity to all CAs as compared with binding data for nonchlorinated compounds. The compounds have a potential for further development of CA inhibitors with higher selectivity for a particular CA isozyme.